The purpose of this investigation is to assess the role of prostaglandins in macrophage activation. We have shown that LPS treatment of elicited macrophages resulted in an increase in cytolytic activity that was inhibited by indomethacin. The tumoricidal activity directly correlated with the PGE2 produced by the macrophage. Activation of macrophages results in a loss of cAMP-dependent protein kinase I. This observation may explain the observation that inhibition of antitumor activity by PGE2 appears to be independent of an increase of cAMP. Further studies indicate that Ia expression by macrophages can be continuous depending on the nature of the stimulus used to induce Ia. Further, expression of Ia is not inhibited by PGE2. Treatment of macrophages with lymphokine, which results in the transient expression of Ia, is inhibited by PGE2. These results indicate that the nature of the effect of PGE2 on the mononuclear phagocyte depends, in part, on the sequence of prior signals received by the cell. (MB)